The present invention relates to novel compounds and compositions, and methods of their use in the treatment of glaucoma and ocular hypertension. In particular, the present invention relates to the use of certain substituted tetrahydrofuran analogs of D and F series prostaglandins to treat glaucoma and ocular hypertension.
Glaucoma is a progressive disease which leads to optic nerve damage, and, ultimately, total loss of vision. The causes of this disease have been the subject of extensive studies for many years, but are still not fully understood. The principal symptom of and/or risk factor for the disease is elevated intraocular pressure or ocular hypertension due to excess aqueous humor in the anterior chamber of the eye.
The causes of aqueous humor accumulation in the anterior chamber are not fully understood. It is known that elevated intraocular pressure (xe2x80x9cIOPxe2x80x9d) can be at least partially controlled by administering drugs which reduce either the production of aqueous humor within the eye, such as beta-blockers and carbonic anhydrase inhibitors, or increase the flow of aqueous humor out of the eye, such as miotics and sympathomimetics.
Most types of drugs conventionally used to treat glaucoma have potentially serious side effects. Miotics such as pilocarpine can cause blurring of vision and other visual side effects, which may lead either to decreased patient compliance or to termination of therapy. Systemically administered carbonic anhydrase inhibitors can also cause serious side effects, such as nausea, dyspepsia, fatigue, and metabolic acidosis, which side effects can affect patient compliance and/or necessitate the termination of treatment. Moreover, some beta-blockers have increasingly become associated with serious pulmonary side effects attributable to their effects on beta-2 receptors in pulmonary tissue. Sympathomimetics may cause tachycardia, arrhythmia and hypertension. There is therefore a continuing need for therapies which control the elevated intraocular pressure associated with glaucoma.
Prostaglandins, which are metabolite derivatives of arachidonic acid, have recently been pursued for possible efficacy in lowering IOP. Arachidonic acid in the body is converted to prostaglandin G2, which is subsequently converted to prostaglandin H2. Other naturally occurring prostaglandins are derivatives of prostaglandin H2. A number of different types of prostaglandins have been discovered including A, B, D, E, F, G, I and J-series prostaglandins (EP 0 561 073 A1). Of interest in the present invention are compounds which are believed to exhibit IOP lowering mechanisms similar to those exhibited by PGD2 (formula (I)) and PGF2xcex1, (formula (II)): 
The relationship between prostaglandin DP receptor activation and IOP lowering effects is not well understood. Various publications have reported that DP receptor activation leads to second messenger activation and in particular, to the stimulation of adenylate cyclase and resultant increases in cAMP levels (Thierauch, Prostaglandins and their Receptors: II. Receptor Structure and Signal Transduction, Journal of Hypertension, volume 12, pages 1-5 (1994). Regardless of mechanism, PGD2 has been shown to lower IOP (Nakajima, Effects of Prostaglandin D2 and its analog, BW245C, on Intraocular Pressure in Humans, Graefe""s Archive Ophthalmology, volume 229, pages 411-413 (1991)). Thus, it has been of interest in the field to develop synthetic PGD2 analogs with IOP lowering efficacy.
Synthetic PGD2-type analogs have been pursued in the art (Graefe""s Archive Ophthalmology, volume 229, pages 411-413 (1991)). Though some PGD2-type molecules lower IOP, these types of molecules have also been associated with undesirable side effects resulting from topical ophthalmic dosing. Such effects have included an initial increase in IOP, conjunctival hyperemia, increases in microvascular permeability, and increases in eosinophile infiltration (Alm, The Potential of Prostaglandin Derivatives in Glaucoma Therapy, Current Opinion in Ophthalmology, volume 4, No. 11, pages 44-50 (1993)).
Similarly, the relationship of prostaglandin FP receptor activation and IOP lowering effects is not well understood. It is believed that FP receptor activation leads to increased outflow of aqueous humor. Regardless of mechanism, PGF2xcex1, and some of its analogs have been shown to lower IOP (Giuffre, The Effects of Prostaglandin F2xcex1, the Human Eye, Graefe""s Archive Ophthalmology, volume 222, pages 139-141 (1985); and Kerstetter et al., Prostaglandin F2xcex1-1-Isopropylester Lowers Intraocular Pressure Without Decreasing Aqueous Humor Flow, American Journal of Ophthalmology, volume 105, pages 30-34 (1988)). Thus, it has been of interest in the field to develop synthetic PGF2xcex1 analogs with IOP lowering efficacy.
Synthetic PGF2xcex1-type analogs have been pursued in the art (Graefe""s Archive Ophthalmology, volume 229, pages 411-413 (1991)). Though PGF2xcex1-type molecules may lower IOP, these types of molecules have also been associated with undesirable side effects resulting from topical ophthalmic dosing. Such effects include an initial increase in IOP, breakdown of the blood aqueous barrier and conjunctival hyperemia (Alm, The Potential of Prostaglandin Derivatives in Glaucoma Therapy, Current Opinion in Ophthalmology, volume 4, No.11, pages 44-50 (1993)).
Based on the foregoing, a need exists for the development of molecules that may activate the prostaglandin DP and/or FP receptors, yielding a more efficacious lowering of IOP, while exhibiting fewer or reduced side effects.
An agent which exhibits comparable or improved efficacy, but with reduced side effects when compared to other agents, is said to have an improved therapeutic profile. It is an object of this invention to provide a class of lOP lowering agents with an improved therapeutic profile over endogenous prostaglandins, and methods of their use.
The present invention is directed to compositions and methods of their use in treating glaucoma and ocular hypertension. In particular, the present invention provides certain classes of substituted tetrahydrofurans which may possess functional DP and/or FP receptor agonist activity, and methods of their use in treating glaucoma and ocular hypertension.
It has unexpectedly been found that substituted tetrahydrofurans of the present invention exhibit an improved therapeutic profile in the treatment of glaucoma and ocular hypertension when compared to natural prostaglandins and many of their known analogs. The substituted tetrahydrofurans of the present invention are heptanoic acid derivatives having the following formula (III): 
wherein:
R=pharmaceutically acceptable ester moiety, CO2R1, CONR7R8, CH2OR9, or CH2NR10R11, where R1=H or cationic salt moiety; R7 and R8 are the same or different=H or alkyl; R9=H, acyl, or alkyl; and R10 and R11 are the same or different=H, acyl, or alkyl; with the proviso that if one of R10 and R11=acyl, then the other=H or alkyl;
n=0 or 2; 
wherein:
Y=CH2CHxe2x95x90CH (cis olefin), CHxe2x95x90CHCH2 (cis olefin), or CH2CH2CH2;
Z=Cxe2x89xa1C, trans CHxe2x95x90CH, or CH2CH2;
Y2=halogen or alkoxy;
X2=O, S, or CH2; and
A=cis CHxe2x95x90CH, CH2CH2, or Cxe2x89xa1C;
one of R2 and R3=H, and the other=F or OH, where the OH may be free or functionally modified; or R2 and R3 taken together=OCH2CH2O or double bonded O (carbonyl); and
R4=cyclohexyl, linear or branched C5-C7 alkyl, or R5, wherein:
R5=(CH2)mXphenyl or (CH2)p Z2, where X=O or CH2; m=1-6; the phenyl is either unsubstituted or substituted with R6, where R6=halogen, CH3, CF3, CN, OCH3 or acetyl; p=0-6; and 
wherein:
W=O, CH2, CH2CH2, or CHxe2x95x90CH; and R6 is as defined above;
provided that when G is (i) then R4=R5, and when G is (ii) or (iii) then R4=cyclohexyl, linear or branched C5-C7 alkyl, and R2, R3are different=H and OH.
For purposes of the foregoing and following definitions, the term xe2x80x9cpharmaceutically acceptable ester moietyxe2x80x9d means any ester moiety that would be suitable for therapeutic administration to a patient by any conventional means without significant deleterious health consequences. Similarly, the term xe2x80x9cophthalmically acceptable ester moietyxe2x80x9d means any pharmaceutically acceptable ester moiety that would be suitable for ophthalmic application, i.e. non-toxic and non-irritating. Preferred are ophthalmically acceptable esters such as alkyl and alkylcycloalkyl esters of carboxylic acids. Most preferred are C2-C5 alkyl esters of carboxylic acids, and especially isopropyl esters.
Preferred compounds of the present invention are those of formula IV: 
wherein:
R1=H, or C2-C5 linear or branched alkyl;
Y=CH2CHxe2x95x90CH (cis olefin), CHxe2x95x90CHCH2 (cis olefin), or CH2CH2CH2;
Z=Cxe2x89xa1C, trans CHxe2x95x90CH, or CH2CH2;
one of R2 and R3=H, and the other=F or OH, where the OH may be free or functionally modified; or R2 and R3 taken together=OCH2CH2O or double bonded O (carbonyl); and
R5=(CH2)mXphenyl or (CH2)p Z2, where X=O or CH2; m=1-6; the phenyl is either unsubstituted or substituted with R6, where R6=halogen, CH3, CF3, CN, OCH3 or acetyl; p=0-6; and
Z2=
wherein:
W=O, CH2, CH2CH2, or CHxe2x95x90CH; and R6 is as defined above.
Other preferred compounds of this invention include those of formula V: 
wherein:
R1=H or C2-C5 linear or branched alkyl;
X2=O ,or CH2;
A =cis CHxe2x95x90CH, CH2CH2, or Cxe2x89xa1C;
Y2=halogen;
Z=Cxe2x89xa1C, trans CHxe2x95x90CH, or CH2CH2;
R2, R3 are different=H, and OH; and
R4=cyclohexyl, or C5-C7 linear or branched alkyl.
Especially preferred compounds of this invention are:
The PGD2 type analogs of the present invention (i.e. Compound III, wherein G is (ii) or (iii)) are believed to be novel.
With the exception of: methyl (5Z,13E,15R)-9xcex1-acetoxy-15-hydroxy-17-(3-trifluoromethylphenyl)-11-oxa-18,19,20-trinorprosta-5,13 -dienoate and methyl (5Z,13E,15S)-9xcex1-acetoxy-15-hydroxy-17-(3-trifluoromethylphenyl)-11-oxa-18,19,20-trinorprosta-5,13-dienoate, syntheses of which have been reported by Verdoorn, et al., S. African J. Chem., 40:134-138 (1987), the PGF2xcex1-type analogs useful in the present invention (i.e. Compound III, wherein G is (i)) are also believed to be novel. Related 11-oxa PGFs outside the scope of the present invention are, however, known and their syntheses are described in the literature. The 11-oxa analogs of PGF2xcex1 and PGF2xcex2 are disclosed in Hanessian, et al., Carbohydrate Research, 141:221-238 (1985); and Thiem et al., Liebigs Ann. Chem., 2151-2164 (1985). Arndt, et al., S. African J. Chem., 34:121-127 (1981), and U.S. Pat. No. 4,133,817, similarly disclose 11-oxa analogs of PGF2xcex1. The entire contents of these references are hereby incorporated herein.
In the foregoing illustrations, as well as those provided hereinafter, wavy line attachments indicate that the configuration may be either alpha (xcex1) or beta (xcex2). The dashed lines on bonds between carbons, e.g. in the bicyclic structural formula for Z2, indicate a single or double bond. Two solid lines present between carbons specify the configuration of the relevant double bond. Hatched lines indicate the xcex1 configuration, and a solid triangular line indicates the xcex2 configuration.